THE LASSA FEVER STORY Abdulrazaq G. Habib Infectious & Tropical Diseases Unit College of Health Sciences Bayero University & Aminu Kano Teaching Hospital Kano, Nigeria (Member WHO-Nigerian Immunization Technical Advisory Group) President www.nigerianidsociety.com Bayero University Kano Nigeria

Fauci A (2001). Global emerging and reemerging infectious diseases

Lassa 4/26/2017

Lassa fever 12 Jan 1969- 1st recognised case an American missionary nurse in Lassa, NE- Nigeria 25 Jan 1969- Air lifted to Evangel. Hospital Jos, N. Nigeria 26 Jan 1969- Pt was cared by two american nurses but died that day One of the two caring nurses fell sick after an 8d IP and died after an illness lasting 11d 20 Feb 1969- Head Nurse of the hospital where autopsy for 1st case was done fell sick Pt evacuated to USA by air on a commercial Boeing 707, separated with curtain only Pt recovered after severe protracted illness at ICU of Columbia University NY

Lassa fever A virus was isolated and later named Lassa at Yale Arbovirus Research (YAR) Unit 9 Jun 1969- One of YAR virologists fell ill and survived only as a result of an immune plasma transfusion donated by the surviving third case 30 Nov 1969- A Laboratory technician at YAR fell ill and died Jan-Feb 1970- a devastating hospital outbreak at Vom and Jos: Outbreak affected 28 patients with 12 deaths, including the American doctor who first identified the disease and did autopsies

General Facts Viral hemorrhagic fever caused by the Arenavirus Lassa Transmitted from rodents to humans Discovered in Nigeria, 1969 Endemic in portions of West Africa Seasonal clustering: Late rainy and early dry season Affects all age groups and both sexes

Arenaviridae Name derived from “arenosus” (Latin “sandy”) describing appearance of virions on examination by electron microscopy Enveloped virus, round or pleomorphic, 50-300 nm in diameter Single-stranded genome divided into 2 RNA segments: small (~3.4 kb) and large (~7.1 kb) 2 genes on each segment, arranged in unique “ambisense” orientation, encoding 5 proteins Inactivated by: heating to 56oF pH<5.5 or >8.5 UV/gamma irradiation detergents

Arenaviridae Arenaviruses associated with human disease Virus Origin of Name Year Distribution Lassa Town, Nigeria 1969 West Africa Junin Town, Argentina 1957 South America Machupo River, Bolivia 1962 South America Guanarito Area, Venezuela 1989 South America Sabia Town, Brazil 1990 South America LCMV Clinical disease 1933 Worldwide

Lassa Virus Image source: C.S. Goldsmith and M. Bowen (CDC).

Epidemiology Endemic in areas of West Africa, including Nigeria, Liberia, Sierra Leone, and Guinea Estimated 300,000-500,000 infections/year, with 5000 deaths Rodent-to-human transmission (the “multimammate rat”, Mastomys species-complex) Secondary human-to-human transmission with the potential for nosocomial outbreaks with high case-fatality

CDC undertook serological studies in Sierra Leone 2.2 cases/1000 inhabitants Some areas had seroprevalence of 52% Most infections benign 200,000-300,000 cases p.a. 5,000-10,000 deaths p.a. 4/26/2017

LASSA FEVER IN WEST AFRICA Fichet-Calvet & Rogers 2009

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States that reported Lassa fever 2007/2008

Current Nigerian epidemic: Kano Started Nov 2015 Two patients admitted 3rd / 4th December Diagnosis came out Lassa Fever 112 people had contacted them, 75% HCW 4 had symptoms, positive sera and on Ribavirin Unguwa Uku, Tiga and Bunkure 38 being monitored now Rijiyar Lemo? (A case in 2012?) 4/26/2017

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2015 Wk 42: 337 cases, 13 lab confirmed, 7 dead, CFR2.08% Taraba, Rivers 4/26/2017

Epidemiology in Nigeria Many cases of Lassa fever are un accounted Poor lab support Inadequate surveillance systems 4/26/2017

KANO DATA AS AT 18th JANUARY 2016 Description Garun Mallam Tarauni Kura Bebeji Bunkure Fagge Dala Gwale Kumbotso KMC Gwarzo Shanono T/Wada Rano Total New Cases   New Confirmed New Probable New Suspected Cumulative Cases Total Confirmed 2 Total Probable Total Suspected 5 1 14 7 16 Total No. currently in isolation Deaths Newly Reported on 18th Jan 2016 Total Deaths in Confirmed cases Total Deaths in Probable cases Total Deaths in suspected cases Total Deaths 3 9 Contacts New Contacts listed on 18th Jan 2016 Cumulative contacts listed 45 115 29 34 4 12 6 27 306 Contacts currently under follow up 11 87 Contacts seen on 18th Jan 2016 26 Contacts who completed 21 days FU 78 24 23 188 Contacts lost to follow Up 61 Contact Dropped after negative result 31 Laboratory Specimen collected on 18th Jan 2016 Specimen Pending testing Total Specimen tested 8

Known Distribution of Mastomys LASSA 1969

Reservoir 4/26/2017

Rodent Reservoir Mastomys species complex Taxonomy still unclear M. huberti: more common in peridomestic habitat M. erytholeucus: more common in brush habitat Others

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Transmission Rodent-to-human: Inhalation of aerosolized virus Ingestion of food or materials contaminated by infected rodent excreta Catching and preparing Mastomys as a food source

Transmission Human-to-human: Direct contact with blood, tissues, secretions or excretions of infected humans Needle stick or cut Inhalation of aerosolized virus

Pathogenesis Endothelial cell damage/capillary leak Platelet dysfunction Suppressed cardiac function Cytokines and other soluble mediators of shock and inflammation

Clinical Aspects Incubation period of 5-21 days Gradual onset of fever, headache, malaise and other non-specific signs and symptoms Pharyngitis, myalgias, retro-sternal pain, cough and gastrointestinal symptoms typically seen A minority present with classic symptoms of bleeding, neck/facial swelling and shock Case fatality of hospitalized cases: 15-20% Particularly severe in pregnant women and their offspring Deafness a common sequela

Clinical Signs and Symptoms Fever Headache Arthralgias/Myalgias Retro-sternal Pain Weakness Dizziness Sore throat/Pharyngitis Cough Vomiting Abdominal Pain/Tenderness Diarrhea Conjunctivitis/Sub-conjunctival Hemorrhage Chills Deafness Lymphadenopgathy Bleeding Confusion Swollen Neck or Face 10 20 30 40 50 60 70 80 90 100 Percent

Lassa Fever in Pregnancy Increased maternal mortality in third trimester (>30%) Increased fetal and neonatal mortality (>85%) Increased level of viremia in pregnant women Placental infection Evacuation of uterus improves mother’s chance of survival

Sensorineural Hearing Deficit in Lassa Fever Typically appears during early convalescence Not related to severity of acute illness Occurs in one-third of cases May be bilateral or unilateral May persist for life in up to one-third of those affected

Lassa Fever in Children and Infants Significant cause of pediatric hospitalizations in some areas of West Africa Signs and symptoms most often similar to adults “Swollen Baby Syndrome” - Edema/Anasarca - Abdominal distension - Bleeding - Poor prognosis

Differential Diagnosis of Lassa Fever Malaria Typhoid fever Streptococcal pharyngitis Leptospirosis Bacterial sepsis Bacterial meningitis Arboviral infection Anicteric hepatitis Enterovirus infection Bacterial or viral conjuctivitis

Diagnostics Clinical diagnosis often difficult ELISA (Enzyme-linked immunosorbent assays) for antigen, IgM, and IgG As research tools: Virus isolation Immunohistochemistry (for post-mortem diagnosis) RT-PCR (Reverse transcription-polymerase chain reaction)

Treatment General support Fluids and electrolytes Antipyretics Oxygen Intensive care (Antibiotics) Ribavirin Infection control Barrier nursing Report! 4/26/2017

Treatment Supportive measures Ribavirin Most effective when started within the first 6 days of illness Major toxicity: mild hemolysis and suppression of erythropoesis. Both reversible Presently contraindicated in pregnancy, although may be warranted if mother’s life at risk Does not appear to reduce incidence or severity of deafness

Ribavirin dose Loading dose 2g 1g 6 hourly x 4d 500mg 6 hourly days 5-10 30mg/kg, 15mg/kg, 7mg/kg 4/26/2017

Side effects Fatigue, headache, alopecia, fever, anxiety, N. V, D, impaired concentration Haemolytic anaemia Neutropenia Thrombocytopenia Embryocide Suicide ideation Pregnancy benefits Vs risks Hypersensitivity 4/26/2017

Associated with Poor Prognosis in Lassa Fever High viremia Serum AST level >150 IU/L Bleeding Encephalitis Edema Third trimester of pregnancy

Nosocomial Lassa fever in Nigeria Fisher-Hoch SP, Tomori O, Nasidi A et al. BMJ 1995; 311: 857-9 Two hospital outbreaks in Imo state 34 patients 6 nurses; 2 surgeons; 1 physician Diagnosis: All clinically consistent; 11 serological; 5 virus isolation Attack rate = 55% 22 deaths (65%) Likely cause: Parenteral drug rounds and sharing of needles Inference: Elucidates the high price of poor medical practice Key points: High priority must be given to education of medical staff, equiping hospitals, promoting infection control practices and use of guidelines for safe operation of clinics and hospitals in developing countries.

Prevention Early patient identification Barrier nursing Universal precautions PPE Waste disposal Rodent control Rodent hunting/ eating No vaccine 4/26/2017

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Prevention and Control Village-based programs for rodent control and avoidance Hospital training programs to avoid nosocomial spread: barrier nursing manual Diagnostic technology transfer Specific antiviral chemotherapy (ribavirin)

Rodent Control Proper storage of food in rodent-proof containers Cleaning around homes Trapping and killing rodents with proper and safe disposal of carcasses Avoid rodents as a food source

Negative Pressure Isolation Room This slide shows the layout of a negative pressure isolation room. On the far right side is the hallway or general access area. This leads into a front room or antechamber of the isolation room. The antechamber can be used for changing into the appropriate personal protective equipment, and for monitoring the patient without contacting the patient. This room leads into the isolation room. Both the change room and the isolation room contain disinfection stations for washing hands and using hand-wash alcohol dispensers. This isolation room is negative pressure, so that air is ventilated to the outdoors and not circulated in the rest of the hospital.

Natural Ventilation Cohorting Room 1 meter This slide shows the ventilation system that might be used if a negative pressure isolation room is not available. Air flows into the room from the outdoors, and flows back out of the room to the outdoors. There should be a door that can be kept closed. If multiple patients are cohorted in the same room, beds should be kept at least one meter apart.

Use PPE on patient contact Now let’s take a break from the lecture to practice safely donning and removing PPE. First, your instructor will demonstrate the appropriate method of donning and safely removing PPE. You will then have an opportunity to practice the procedures both alone and with a partner. Facilitator Note: Demonstrate procedures as indicated, or have a designated person conduct the demonstration. Narrate to trainees as each piece of equipment is donned and removed. Put on and Remove PPE

PAPRs are available

Ongoing Lassa Fever Research in Guinea, West Africa Natural history of disease Where it came from How clinical course progresses Whom it affects Diagnosis: Clinical/Laboratory Immunopathogenesis Treatment Rodent population dynamics Prevention and control Collaboration between CDC/SPB and the Guinean Institute for Research and Applied Biology

Infections as Strategic and Security issue: Daniel Defoe’s Journal – A Visitation of The Plague ‘It was indeed, that man withered like grass and that his brief earthly existence became a fleeting shadow. Contagion was rife in all our streets and so baleful were its effects, that the church yards were not sufficiently capacious to receive the dead. It seemed for a while as though the brand of an avenging angel had been unloosed in judgement ….’ ‘..panic spread over the city of London. Trapped by poverty, a gullible populace became prey to an army of astrologers, charlatans and quack doctors who offered false promises of hope in the face of impending horror’

Distribution of Reported Epidemics in Nigeria from 2003 – 2007 and Jan 2008 KEY Cholera/Gastro Enteritis 2003 2004 2005 2006 2007 CSM 2003 2004 NE Measles Lassa Fever 2005 Yellow Fever 2003 2003 2006 2004 2007/2008 2004 2005 2007 2005 2006 AI Human 2006 2007/2008 2007/2008 2007 NE: No Epidemics reported

“Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever” William Osler Thank you